1,2,3,6-tetrahydro-4-pyridylmethyl carboxylates

ABSTRACT

RACEMIC MIXTURES OF COMPOUNDS OF THE FORMULA   1-R1,4-(R2-COO-CH2-)-1,2,3,6-TETRAHYDROPYRIDINE   WHEREIN R1 IS HYDROGEN, ALKYL OF 1 TO 8 CARBON ATOMS, CHLORO(ALKYL OF 1 TO 8 CARBON ATOMS), CYANO-(ALKYL OF 1 TO 8 CARBON ATOMS), HYDROXY-(ALKYL OF 1 TO 8 CARBON ATOMS), PHENYL-(ALKYL OF 1 TO 8 CARBON ATOMS), ALKENYL OF 3 TO 4 CARBON ATOMS OR ALKINYL OF 3 TO 4 CARBON ATOMS, AND R2 IS   -C(-R3)(-R4)-C6H5, -CH(-R5)-R6, FLUOREN-9-YL OR   XANTHEN-9-YL   WHERE R3 IS HYDROXYL OR, TOGETHER WITH R4 AND THE CARBON ATOM TO WHICH THEY ARE ATTACHED, A 5- TO 6-MEMBERED SATURATED CARBOXYLIC RING, R4 AND R5 ARE EACH ALKYL OF 1 TO 4 CARBON ATOMS, CYCLOALKYL OF 5 TO 6 CARBON ATOMS OR PHENYL, AND R6 IS CYCLOALKYL OF 5 TO 6 CARBON ATOMS OR PHENYL, OPTICALLY ACTIVE ANTIPODES THEREOF, QUARTERNARY AMMONIUM SALTS THEROF, AND NON-TOXIC ACID ADDITION SALTS OF SAID RACEMATES AND OPTICALLY ACTIVE ANTIPODES; THE COMPOUNDS ARE USEFUL AS ANTICHOLINGERICS.

United States Patent U.S. Cl. 260-295 R 4 Claims ABSTRACT OF THE DISCLOSURE Racemic mixtures of compounds of the formula wherein R is hydrogen, alkyl of 1 to 8 carbon atoms, chloro- (alkyl of 1 to 8 carbon atoms), cyano-(alkyl of 1 to 8 carbon atoms), hydroxy-(alkyl of 1 to 8 carbon atoms),

phenyl-(alkyl of 1 to 8 carbon atoms), alkenyl of 3 to 4 carbon atoms or alkinyl' of 3 to 4 carbon atoms, and R2 iS where R is hydroxyl or, together with R and the carbon atom to which they are attached, a 5- to 6-membered saturated carbocyclic ring, R, and R are each alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 6 carbon atoms or phenyl, and R is cycloalkyl of 5 to 6 carbon atoms or phenyl,

opticallyactive antipodes thereof, quaternary ammonium salts thereof, and non-toxic acid addition salts of said racemates and optically active antipodes; the compounds are useful as anticholinergics. 1 a

.Thisinyention relates to novel 1,2,3,6 -tetrahydro-4-pyridyhnethyl carboxylates, acid addition salts thereof and quaternary salts thereof, as well as to various methods of preparing these compounds.

I More particularly, the present invention relates to a novel class of racemic and optically active compounds of the formula a 3 wherein 3,786,059 Patented Jan. 15, 1974 wherein R is hydrogen, alkyl of 1 to 8 carbon atoms, chloro- (alkyl of 1 to 8 carbon atoms), cyano-(alkyl of 1 to 8 carbon atoms), hydroxy-(alkyl of 1 to 8 carbon atoms), phenyl-(alkyl of 1 to 8 carbon atoms), alkenyl of 3 to 4 carbon atoms or alkinyl of 3 to 4 carbon atoms, and

R2 is where R; is hydroxyl or, together with R, and the carbon atom to which they are attached, a 5- to 6-membered saturated carbocyclic ring, R, and R are each alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 6 carbon atoms or phenyl, and R is cycloalkyl of 5 to 6 carbon atoms or phenyl,

non-toxic, pharmacologically acceptable acid addition salts thereof and quaternary salts thereof.

The compounds embraced by Formula I above may be prepared by a number of diiTerent methods involving Well known chemical synthesis principles, among which the following have proved to be most convenient and efiicient.

Method A By esterifying a 1,2,3, 6-tetrahydro 4 pyridylmethyl compound of the formula CH2X X is hydroxyl or halogen, and

R, has the same meanings as in Formula I, but is preferably alkyl of 1 to 8 carbon atoms, cyano-(alkyl of l to 8 carbon atoms), pheny1-(alky1 of 1 to 8 carbon atoms) or alkenyl of 3 to 4 carbon atoms,

or an acid addition salt thereof, with a compound of the formula 0 Rr-HJ-Y wherein R has the same meanings as in Formula I, and Y is acyloxy, preferably carboxylic acyloxy, N-imidazolyl,

halogen, hydroxyl or -ONa.

, a Method B By reacting a 1,2,3,6-tetrahydro-4-pyridylmethyl-carbinol of the formula onion i R1 (Ha) wherein R, has the same meanings as in Formula I, but is preferably alkyl of 1 to 8 carbon atoms, phenyl-(alkyl of 1 R has the same meanings as in R is lower alkyl,

in the presence of a basic catalyst, such as an alkali metal alcoholate.

Formula I, and 7 Method C By alkylating a 1,2,3,6-tetrahydro-4-pyridylmethyl carboxylate of the formula wherein R has the same meanings as in Formula I, with an alkyl halide of the formula (VI) wherein X is halogen, and R has the same meanings as in Formula I,

pursuant to conventional methods, or with a corresponding aldehyde in the presence of formic acid.

Method D For the preparation of a compound of the Formula I wherein R is chloroalkyl, by reacting an 'N-hydroxyalkyl 1,2,3,6 tetrahydro-4-pyridylmethyl carboxylate of the formula heretofore not been specifically described in the prior art may be prepared'by'known processes.

For instance, a starting compound of the Formula IIa may be prepared by reducing a pyridinium carbinol of the formula onion wherein R, is alkyl or substituted alkyl, and X is halogen, for example, bromine and iodine PREPARATION OF STARTING COMPOUNDS OF THE FORMUL IIa Example A l-methyl-1,2,3,6-tetrahydro-4-pyridyl-carbinol: A solution of 22.8 gm. (0.6 mol) of sodium borohydride in 50 ml. of 0.1 N sodium hydroxide was addedvdropwise over a period of one hour to a solution of 102 gm. (0.5 mol) of 1-methyl-4-hydroxymethyl-pyridinium bromide in 600 ml. of methanol at 5 to 0 C., accompanied by stirring. Thereafter, the reaction solution was stirred for one hour more at 0 C. and was then substantially evaporated in vacuoon a water bath at 60 C. The residue was admixed with aqueous 40% potassium carbonate, and the mixture was extracted several times with ether. The combined ether extract solutions were dried over sodium sulfate and then evaporated, and the residual raw wherein R, has the same meanings as in Formula I, and n is an integer from 2 to 8, inclusive, with a chlorinating agent, such as thionyl chloride.

The compounds of the 'Formula I above are organicbases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with a hydrohalic acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, citric acid, maleic acid, 8-chlorotheophylline or the like.

Likewise, a tertiary tetrahydro-pyridylmethyl carboxylate of the Formula I may be converted into the corresponding quaternary tetrahydro-pyridinium salt by reaction with a conventional quaternizing agent, suchvas an alkyl halide, an alkyl sulfate or an alkyl methanesulfonate.

The compounds embraced by Formula I may occur as racemic mixtures from which the optically active antipode components may be isolated by conventional fractional precipitation procedures with the aid of an optically active acid, such as L(+)- and/or D()-tartaric acid. However, the optically active antipodes may also be obtained directly by using the corresponding optically active starting compounds in Methods A to D' above.

The majority of the starting compounds for Methods A to D are known compounds, and those which have product was fractionally distilled in vacuo, yielding 45.1 gm. (71% of theory) of the compound of the formula CHzOH having a boiling point of 86-88 C. at 0.2 mm. Hg;

-43.7 gm. of the base were dissolved in ethyl acetate and, while exteriorly cooling the solution withice, gaseous hydrogen chloride was passed therethrough. The crystalline precipitate formed thereby was collected by vacuum filtration and recrystallized from ethanol, yielding51.8

.gm. (92% of theory) of the hydrochloride, M.P 152 Example Using a procedureanalogous to that described in Exethyl-4-hydroxymethyl-pyridinium bromide. Its hydrochloride had a melting point of 136-138" C. -(recrystallized from ethanol).

'Example C A B.P. l39142 C. at 17 mm. Hg, was prepared from l-npropyl-4-hydroxymethyl-pyridinium bromide. Its hydro.

Example E Using a procedure analogous to that descirbed in Example A, 1-n-butyl-l,2,3,6-tetrahydro-4-pyridyl-carbinol, B.P. 146-149" C. at 17 mm. Hg, was prepared from l-nbutyl-4-hydroxymethyl-pyridinium bromide. Its hydrochloride had a melting point of 153-156 C. (recrystallized from acetonitrile).

Example F Using a procedure analogous to that described in Example A, l-n-pentyl-1,2,3,6-tetrahydro-4-pyridyl-carbinol, B.P. 159-1=63 C. at 17 mm. Hg, was prepared from l-npentyl-4-hydroxymethyl-pyridinium lbromide. Its hydrochloride had a melting point of 150-151" C. (recrystallized from a acetonitrile/ acetone).

Example G Using a procedure analogous to that described in Example A, l-n-hexyl-1,2,3,6-tetrahydro-4-pyridyl-carbinol, B.P. 169-173 C. at 17 mm. Hg, was prepared from l-nhexyl 4 hydroxymethyl pyridinium bromide. Its hydrochloride had a melting point of 131.5-134 C. (recrystallized from acetonitrile Example H Using a procedure analogous to that described in Example A, 1 allyl1,2,3,6-tetrahydro-4-pyridyl-carbinol, B.P. 143l45 C. at 17 mm. Hg, was prepared from 1- allyl-4-hydroxymethyl-pyridinium bromide. Its hydrochloride had a melting point of 124126 C. 1

Example I Using a procedure analogous to that described in Example A, 1-( B-phenethyl) 1,2,3,6 tetrahydro-4-pyridylcarbinol, M.P. 69.57l C. (recrystallized from acetone/ gasoline), was prepared from l-(p-phenethyl)-4-hydroxymethylpyridinium bromide.

PREPARATION OF END PRODUCTS OF THE FORMULA I Example 1 l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a phenylcyclopentylacetate, its methanesulfonate and its hydrochloride by method A: A mixture consisting of 163.65 gm. (1 mol) of 1-methyl-1,2,3,6-tetrahydro-4-pyridyl-carbinol hydrochloride, 234 gm. (1.05 mol) of a-phenylcyclopentylacetic acid chloride and 400 ml. of absolute pyridine was refluxed for three hours. Thereafter, the pyridine was distilled oil in vacuo, the residue was taken up in 2 N hydrochloric acid, and the resulting acidic solution was extracted twice with 200 ml. of ether each. The ether extracts were discarded, and the acid aqueous phase was made alkaline with concentrated ammonia and extracted twice with 500 ml. of ether each. The combined ethereal extract solutions were dried over anhydrous sodium sulfate and then evaporated, leaving as the residue 299 gm. (95% of theory) of the raw 1-methyl-1,2,3,6- tetrahydro-4-pyridylmethyl ester of u-phenyl-cyclopentylacetic acid.

The raw base was dissolved in 1500 ml. of ether, and 96 gm. of methanesulfonic acid were added dropwise to the solution, while stirring. The crystalline precipitate form/ed thereby was collected by vacuum filtration and recrystallized several times from acetone, yielding 305 gm. (74.6% of theory) of the compound of the formula having a melting point of 128-130 C.

The hydrochloride had a melting point of 15 3-l55 C., (recrystallized from acetone).

Example 2 1-methyl-1,2,3,6 tetrahydro-4-pyridylmethyl-a-phenylcyclopentylacetate and its methanesulfonate by method B: 25.43 gm. (0.2 mol) of l-methyl-1,2,3,6-tetrahydro-4- pyridyl-carbinol and 52.4 gm. (0.24 mol) of methyl aphenyl-cyclopentylacetate (B.P. 1.56159 C. at 17 mm. Hg; 11 :1.5129) were dissolved. in ml. of absolute n-heptane, 1 gm. of sodium methylate was added to the solution, and the mixture was refluxed for three hours while simultaneously continuously withdrawing the methanol released by the ester exchange reaction with the aid of a water separator. Thereafter, the reaction mixture was extracted tfirst several times with. 'water and then twice with ml. of aqueous 50% acetic acid each. The combined acetic acid extracts were made alkaline with concentrated ammonia while exteriorly cooling with ice, and the base liberated thereby was extracted with n-heptane. The heptane extract solution was. thoroughly dried over anhydrous sodium sulfate and then evaporated in vacuo at 60 C., leaving as a residue 53.5 gm. (85.4% of theory) of a light yellow oil, which was identified to be the lmethyl-1,2,3,6-tetrahydro 4 pyn'dylmethyl ester of ozphenyl-cyclopentylacetic acid.

The free base was converted into its methanesulfonate, M.P. 128-130 C., which was identical to the methanesulfonate obtained in Example 1.

EXAMPLE 3 Using a procedure analogous to that described in Example 2, l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl ozphenyl--methyl-butyrate hydrochloride, M.P. 182-185 C. (recrystallized from acetonitrile), of the formula was prepared from -1-methyl-1,2,3 ,6-tetrahydro-4-pyridylcarbinol and methyl a-phenyl-fi-methyl-butyrate.

Example 4 l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a phenylcyclohexylacetate and its methanesulfonate by Method A: A mixture consisting of 88.2 gm. (0.54 mol) of l-methyl- 1,2,3,6 tetrahydro-4-pyridyl-canbinol hydrochloride, 128 gm. (0.54 mol) of a-phenyl-cyclohexylacetic acid chloride and 500 ml. of absolute pyridine was refluxed for three hours. Thereafter, the reaction solution was evaporated in vacuo, the residue was taken up in aqueous 20% hydrochloric acid, and the acid solution was extracted with 300 ml. of ether. The acidic aqueous phase was made alkaline with concentrated ammonia, and the base liberated thereby was separated by extracting the mixture three times with 300 ml. of ether each. The combined ethereal extracts were dried over anhydrous sodium sulfate and then evaporated in vacuo, leaving as a residue 160.5 gm.

(90.7% of theory) of a light yellow oil, which was identified to be the raw l-methyl-l,2,3,6-tetrahydro-4- pyridylmethyl ester of a-phenyl-cyclohexyl-acetic acid.

The free base was dissolved in ether, the solution was admixed with a slight excess of methanesulfonic acid, and the precipitate formed thereby was collected and recrystallized from ethylacetate, yielding the methanesulfonate of the formula -CHaSOaH A Ha having a melting point of 127-129 C.

Example Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro 4 pyridylmethyl 1- phenyl-cyclopentanecarboxylate and its hydrochloride, M.P. 154-155 C. (recrystallized from acetonitrile/ether), of the formula were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and 1 phenyl cyclopentanecarboxylic acid chloride.

Example 6 Using a procedure analogous to that described in Example 4, 1-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl diphenylacetate and its hydrochloride, M.P. 142143 C. (recrystallized from acetonitrile/ether), of the formula were prepared from l-methyl-l,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and diphenylacetic acid chloride. Methobromid: F.P. 155-15 8 C.

Example 7 Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro 4 pyridylmethyl xanthene-9-carboxylate and its methanesulfonate, M.P. ISO-152 C. (recrystallized from butanone), of the for- .CH: S 02H were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and xanthene-9-carboxylic acid chloride.

8 Example 8 Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro-4pyridylmethyl aphenyl- -methyl-valerate and its hydrochloride, MP. 127 C. (recrystallized from ethyl acetate), of the formula were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and a-pheny1-y-methyl-valeric acid chloride.

Example 9 Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl dicyclopentylacetate and its hydrochloride, M.P. 147-148 C. (recrystallized from acetone/ether), of the formula were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and dicyclopentylacetic acid chloride.

Example 10 'Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro-4-pyridyl methyl a-nbutyl-cyclopentylacetate and its tartrate, M.P. 103-106" C. (recrystallized from acetonitrile), of the formula CHz-O-E-CH E y N (SH: were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol hydrochloride and a n butyl-cyclopentylacetic acid chloride.

Example 11 Using a procedure analogous to that described in Example 4, l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl u-phenyl-butyrate and its citrate, M.P. 122-124" C. (recrystallized from isopropanol), of the formula phenyl-cyclopentylacetate and its. hydrochloride, M.P.

9 143-145 C. (recrystallized from ethylacetate), of the formula CH10i .-OH- HI 6 were prepared from l-isopropyl-1,2,3,6-tetrahydro-4- pyridylcarbinol hydrochloride and a-phenyl-cyclopentylacetic acid chloride.

Example 13 1-methyl-1,2,3,6-tetrahydro 4-pyridylmethyl a-phenylcyclopentylacetate methobromide: A mixture consisting of 15.7 gm. (0.05 mol) of l-methyl-1,2,3,6-tetrahydro-4- pyridylmethyl u-phenyl-cyclopentylacetate, 7.13 gm. (0.075 mol) of methyl bromide and 50 ml. of acetonitrile was stirred for four hours at room temperature. Thereafter, the crystalline precipitate formed thereby was collected by vacuum filtration and repeatedly recrystallized from acetonitrile until it had a constant melting point. 15.3 gm. (75% of theory) of the quaternary salt, M.P. 185-187 C., of the formula a; H39 CHa were obtained.

Example 14 Using a procedure analogous to that described in Example 13, l-methyl-l,2,3,6-tetrahydro-4-pyridyl-rnethyl acyclopentyl-phenylglycolate methobromide, M.P. 200- 203 C. (recrystallized from acetom'trile), of the formula H30 CH:

was prepared from I-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-cyclopentyl-phenylglycolate and methyl bromide.

Example 15 Using a procedure analogous to that described in Example 13, l-ethyl-1,2,3,6-tetrahydro4-pyridylmethyl benzilate methobromide, M.P. 145-147 C. (recrystallized from acetonitrile), of the formula was prepared from l-ethyl-l,2,3,6-tetrahydro-4-pyridylmethyl benzilate and methyl bromide.

10 Example 16 Using a procedure analogous to that described in Example 13, l-allyl-l,2,3,6-tetrahydro-4-pyridylmethyl benzilate methobromide, M.P. 153-155 C. (recrystallized from acetonitrile), of the formula was prepared from 1-allyl-1,2,3,6-tetrahydro-4-pyridylmethyl benzilate and methyl bromide.

Example 17 Using a procedure analogous to that described in Example 13, l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl 1-phenyl-cyclopentanecarboxylate methobromide, M.P.

184-186 C. (recrystallized from acetonitrile), of the formula 0 CHPO-HF-C -Br 69 1130 CH3 was prepared from 1-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl l-phenyl-cyclopentanecarboxylate and methyl bromide.

Example 18 Using a procedure analogous to that described in Example 13, l-ethyl-1,2,3,6-tetrahydro-4-pyridylmethyl hexahydrobenzilate methobromide, M.P. 177-179 C. (recrystallized from acetonitrile/ether), of the formula 0 0 CaHs was prepared from 1-methyll,2,3,6-tetrahydro-4-pyridylmethyl dicyclopentylacetate and methyl bromide.

Example 20 Using a procedure analogous to that described in Example 13-, l-isopropyl-1,2,3,6-tetrahydro-4-pyridylmethyl 1 1 benzilate methobromide, M.P. 146148 C. (recrystallized from acetonitrile/ethylacetate), of the formula was prepared from l-isopropyl-1,2,3,6-tetrahydro-4-pyr1- dylmethyl benzilate and methyl bromide.

Example 21 l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenylcyclohexylacetate rnethobromide: A mixture consisting of 16.37 gm. (0.05 mol) of l-methyl-1,2,3,6-tetrahydro-4- pyridylmethyl a-phenyl-cyclohexylacetate, 7.13 gm. (0.075 mol) of methyl bromide and 250 ml. of acetone was stirred at room temperature for three hours. Thereafter, the crystalline precipitate which had formed was collected by vacuum filtration and recrystallized from ethanol/ether in the presence of activated charcoal, yielding 16.8 gm. (79.6% of theory) of the quaternary compound, M.P. ZOO-202 C., of the formula Example 22 1-ethyl-1,2,3,G-tetrahydro 4 pyridylmethyl benzilate and its hydrochloride by Method B: 26.7 gm. (0.11 mol) of methyl benzilate and 100 mgm. of sodium methylate were added to a solution of 14.1 gm. (0.1 mol) of l-ethyl- 1,2,3,6-tetrahydro-4-pyridyl-carbinol in 100 ml. of absolute n-heptane, and the mixture was heated at its boiling point for three hours, accompanied by stirring, while simultaneously and continuously withdrawing the methanol released by the esterification reaction with the aid of a water separator. Thereafter, the hot reaction mixture was filtered through activated charcoal to remove insoluble components, the filtrate was allowed to cool, and the crystalline precipitate formed thereby was re-dissolved by addition of ether. The resulting solution was extracted with dilute hydrochloric acid, the acid aqueous phase was made alkaline with concentrated ammonia while exteriorly cooling with ice, and the alkaline mixture was extracted with ether. The ethereal extracts were dried Over anhydrous sodium sulfate and then evaporated in vacuo, and the residue was recrystallized from acetone, yielding 21 gm. (59.8% of theory) of the compound of the formula Example 23 Using a procedure analogous to that described in Example 22, l-methyl-1,2,3,6-tetrahydro-4-pyridylmethy1 acyclopentyl-phenylglycolate and its hydrochloride, MA.

12 -147 C. (recrystallized from acetone), of the f0rmula were prepared from l-methyl-1,2,3,6-tetrahydro-4-pyridylcarbinol and methyl a-cyclopentyl-phenylglycolate.

Example 24 Using a procedure analogous to that described in Example 22, l-n-propyl-1,2,3,G-tetrahydro-4-pyridylmethyl benzilate and its hydrochloride, M.P. 187189 C. (recrystallized from ethanol), of the formula were prepared from l-n-propyl-1,2,3,6-tetrahydro-4-pyridylcarbinol and methyl benzilate.

Example 25 Using a procedure analogous to that described in Example 22, l-isopropyl-1,2,3,6-tetrahydro-4-pyridylmethyl benzilate and its hydrochloride, M.P. 157 C. (recrystallized from acetonitrile/ ether), were prepared from l-isopropyl-1,2,3,6-tetrahydro-4 pyridyl carbinol and methyl benzilate.

Example 26 Using a procedure analogous to that described in Example 22, l-n-hexyl-1,2,3,6-tetrahydro-4-pyridylmethyl benzilate and its hydrochloride, M.P. 146-148 C., were prepared from l-n-hexyl-1,2,3,6-tetrahydro 4 pyridylcarbinol and methyl benzilate.

Example 27 Using a procedure analogous to that described in Example 22, l-allyl-1,2,3,6-tetrahydro 4 pyridylmethyl benzilate and its hydrochloride, M.P. 132134 C. (recrystallized from acetone/ ether), of the formula were prepared from 1-allyl-1,2,3,6-tetrahydro-4-pyridylcarbinol and methyl benzilate.

Example 28 Using a procedure analogous to that described in Example 22, l-(fl-phenethyl)-1,2,3,-6-tetrahydro-4-pyridylmethyl benzilate and its methanesulfonate, M.P. 155- 156 C. (recrystallized from acetonitrile), of the formula N JHrCHr-CaH were prepared from 1-(B-phenethyl)-l,2,3,6-tetrahydro- 4-pyridyl-carbinol and methyl benzilate.

Example 29 Using a procedure analogous to that described in Example 22, l-ethyl 1,2,3,6 tetrahydro-4-pyridylmethyl hexahydrobenzilate and its hydrochloride, M.P. 168-170 C. (recrystallized from acetone/ethylacetate), of the formula O C 0H5 CHz-O-C-iJ-OH were prepared from l ethyl-1,2,3,6-tetrahydro-4-pyridylcarbinol and methyl hexahydrobenzilate.

Example 30 1,2,3,6-tetrahydro 4 pyridylmethyl u-phenyl-cyclopentylacetate hydrochloride: A solution of 15.65 gm. (0.05 mol) of l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate in 40 ml. of absolute toluene was slowly admixed at room temperature with a solution of 5.25 gm. (0.053 mol) of phosgene in 35 ml. of absolute toluene, and the mixed solution was allowed to stand at room temperature for 48 hours. Thereafter, the toluene was distilled ofi at 60 C. in vacuo, the residue was taken up in ether, and the insoluble matter was filtered off. The ethereal filtrate was washed first with 2 N hydrochloric acid and then with water, dried over anhydrous sodium sulfate, and evaporated in vacuo, leaving as a residue 14.65 gm. (81% of theory) of oily l-chlorocarbonyl-l,2,3,6-tetrahydro 4 pyridylmethyl e-phenyl-cyclopentylacetate. This compound was hydrolized by heating it with 70 ml. of water, whereby carbon dioxide was evolved; as soon as all of the oil had gone completely into solution, the hot aqueous solution was filtered through charcoal, and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized several times from acetonitrile in the presence of activated charcoal, yielding 7.1 gm .(42.2% of theory) of the compound of the formula -HCl having a melting point of 162-164 C.

Example 31 l-(B hydroxy-ethyl) 1,2,3,6 tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate hydrochloride by Method C: A mixture consisting of 8.1 gm. (0.024 mol) of 1,2,3,6 tetrahydro 4 pyridylmethyl a-phenylcyclopentylacetate hydrochloride, 3.73 gm. (0.03 mol) of bromoethanol, 5.3 gm. (0.05 mol) of sodium carbonate and 70 ml. of absolute acetonitrile was refluxed for three hours while stirring. Thereafter, the organic salts which had precipitated were filtered off, the acetonitrile was distilled out of the filtrate, and the residue was dissolved in methylene chloride. The resulting solution was shaken with aqueous sodium carbonate, the aqueous phase was separated and extracted with methylene chloride, and the organic phases were combined, dried over sodium sulfate and concentrated by evaporation. Ethereal hydrochloric acid was added to the concentrated methylene chloride solution, and the crystalline precipitate formed thereby was collected by vacuum filtration and repeatedly recrystallized from acetone/ ether until it had a constant melting point. 6.4 gm. (69.9% of theory) of the compound, M.P. 124-124.5 C., of the formula N (kHrCHzOH were obtained.

Example 32 Using a procedure analogous to that described in Example 31, 1-isobutyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate hydrochloride, M.P. 171- 174 C. (recrystallized from acetonitrile/ether), of the formula Was prepared from 1,2,3,6-tetrahydro-4-pyridylmethyl ozphenyl-cyclopentylacetate hydrochloride and isobutyl bromide.

Example 33 Using a procedure analogous to that described in Example 31, 1-propargyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate citrate, M.P. 1l3115 C. (recrystallized from acetone/ether), of the formula 0 CuHtt CHz-O-ii-AIH Hr-CECH was prepared from 1,2,3,6-tetrahydro-4pyridylmethyl aphenyl-cyclopentylacetate hydrochloride and propargyl bromide.

Example 34 Using a procedure analogous to that described in Example 31, 1-(fi-cyano-ethyD-1,2,3,6-tetrahydro-4-pyridylmethyl u-phenyl-cyclopentylacetate hydrochloride, M.P.

15 154-156 C. (recrystallized from acetone/ether), of the formula CoHr N An ara-0N was prepared from 1,2,3,6-tetrahydro-4-pyridylmethyl aphenyl-cyclopentylacetate hydrochloride and ,B-cyanoethyl chloride.

Example 35 Using a procedure analogous to that described in Example 31, l-benzyl-1,2,3,-6-tetrahydro-4-pyridylmethyl aphenyl-cyclopentylacetate hydrochloride, M.P. 185-187 C. (recrystallized from acetonitrile), of the formula (JHr-CuHa was prepared from 1,2,3,6-tetrahydro-4-pyridylmethyl aphenyl cyclopentylacetate and benzyl bromide.

Example 35a 1-ethyl-1,2,3,6-tetrahydro-4-pyridylmethyl-aphenyl-cyelohexylacetate-hydrochloride:

aHs OH The title compound was prepared using a procedure analogous to that described in Example 4, from 1-methyl- 1,2,3,6-tetrahydro-4-pyridylcarbinol-hydrochloride and 2- phenyl-fi-methyl-valeric acid chloride. F .P. 14Z-144.

Example 350 l-methyl-l,2,3,6-tetrahydro-4-pyridylmethylbenzilate-hydrochloride:

O CaHs 16 The title compound was prepared using a procedure analogous to that described in Example 22, from l-methyl-1,2,3,6-tetrahydro-4-pyridyl-carbinol and benzilic acid methyl ester. F.P. 174-175. Methobromide 224-228 C.

Example 36 1- (B chloro-ethyl)-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate hydrochloride by Method D: 3 gm. (0.079 mol) of 1-(B-hydroxy-ethyl)-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl-cyclopentylacetate hydrochloride were dissolved in 20 ml. of thionyl chloride, and the solution was refluxed for 2 /2 hours. Thereafter, the excess thionyl chloride was distilled oil? in vacuo, and the residue was purified by dissolving it three times in acetone and each time distilling ofi the solvent in vacuo. The crystalline product thus obtained was dissolved in hot acetone, reprecipitated therefrom by addition of ether, collected by vacuum filtration, and repeatedly recrystallized from acetone/ether until it had a constant melting point. 2.1 gm. (66.8% of theory) of the compound, M.P. 146 C., of the formula were obtained.

Example 37 Separation of racemic 1,2,3,6-tetrahydro-4-pyridylrnethyl a-phenyl-cyclopentylacetate into optically active antipodes: 76 gm. (0.25 mol) of racemic l,2,3,6-tetrahydro- 4-pyridylmethyl u-phenyl-cyclopentylacetate and 38.2 gm. (0.25 mol) of L(+)-tartaric acid were dissolved in 400 ml. of hot ethanol, and the solution was allowed to cool. The crystalline precipitate formed thereby was collected and recrystallized first twice from a mixture of equal parts of methanol and ethanol and then repeatedly from pure methanol until it had a constant melting point and specific rotation. 36.7 gm. of the tartrate of the dextro-rotatory base, M.P. -l62 C., [a] =+28 (c.=5; dimethylsulfoxide), were obtained.

In like manner, the tartrate of the levo-rotatory base was obtained from the mother liquor of the above precipitation procedure with the aid of D()-tartaric acid. Upon recrystallization from methanol until constant melting point and specific rotation, 24 gm. of the tartrate, M.P. 160-162 C., [u] =28 (c.=5; dimethylsulfoxide) were obtained.

The optically active bases were liberated from the respective tartrates with concentrated ammonia, and converted into the hydrochlorides in conventional fashion, yielding (a) (+)-1,2,3,6-tetrahydro 4 pyridylmethyl u-phenylcyclopentylacetate hydrochloride, M.P. 1215-1235 C. (from acetone/ether), [0c] +30.5 (c.=5; ethanol), and (b) ()-1,2,3,6-tetrahydro 4 pyridylmethyl a-phenylcyclopentylacetate hydrochloride, M.P. 120-122 C.

(from acetone/ether), [a] =30 (c.=5; ethanol).

Example 38 and )-l-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl a-phenyl cyclopentylacetate methanesulfonate from optically active starting compounds by Method C: A mixture consisting of 6 gm. (0.02 mol) of +)-1,2,3,6- tetrahydro-4-pyridylmethyl a-phenyl cyclopentylacetate, 2.5 gm. (0.054 mol) of formic acid and 0.8 gm. of paraformaldehyde was heated for 30 minutes on a boiling water bath. Thereafter, the reaction mixture was allowed to cool, made alkaline with concentrated ammonia, and

17 extracted with ether. The ethereal extract was dried over anhydrous sodium sulfate and then evaporated, leaving as a residue 6.4 gm. (85% of theory) of +)-1-methyl- 1,2,3,6-tetrahydro 4 pyridylmethyl a-phenyl-cyclopentylacetate, whose methanesulfonate had a melting point of 139-141 C. (from acetone) and a specific rotation [a] =+25 (c.=5; ethanol).

In analogous fashion, (-)-l-methyl-l,2,3,6-tetrahydro- 4-pyridylmethyl a-phcnyl-cyclopentylacetate and its methanesulfonate were obtained from the levo-rotatory norbase.

The compounds according to the present invention, that is, those embraced by Formula I above, their non-toxic, pharmacologically acceptable acid addition salts, and their quaternary pyridinium salts, have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit anticholinergic activities in warm-blooded animals, such as dogs, rats and mice.

In comparison to the classic spasmolytic, atropine, the spasmolytic (anticholinergic) activity of the compounds of the instant invention is several times stronger, whereas undesirable side effects, such as mydriasis, tachicardia and inhibition of saliva secretion, become discernable only at 'dosage levels corresponding to several multiples of the therapeutic dose.

Among the tertiary pyridyl compounds represented by Formula I, those wherein R is alkyl of 1 to 3 carbon atoms exhibit an extraordinarily favorable therapeutic ratio between the principal anticholinergic activity and undesirable side efl'ects. Quaternization of these tertiary compounds with an alkyl group, particularly with a moth yl group, further intensifies this therapeutic activity several-fold, while the intensity of the undesirable side effects is, for practical purposes, not intensified.

Especially favorable properties are exhibited by those esters of the Formula I wherein the carboxylate moiety is derived from benzilic acid or zit-phenyl-cycloalkylacetic acid.

For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.0083 to 0.84 mgm./kg. body weight, preferably 0.0166 to 0.33 mgm./kg. body weight.

The following examples illustrate a few dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

Example 39 Coated pills.-The pill core composition is compounded from the following ingredients:

Parts 1 methyl 1,2,3,6 tetrahydro 4 pyridylmethyl a-phenyl-cyclopentylacetate methanesulfonate 10.0 Lactose 57.0 Corn starch 30.0 Gelatin 2.0 Magnesium stearate 1.0

Total 100.0

Preparation: The pyridylmethyl carboxylate salt is intimately admixed with the lactose and the corn starch, the mixture is moistened with an aqueous solution of the gelatin, the moist mass is forced through a 1 rum-mesh screen, the resulting granulate is dried at 40 C. and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into mgm.-pill cores which are subsequently coated with a thin shell consisting essentially of a mixture of sugar, titanium dioxide, talcum and gum arabic, and finally polished with bees-wax. Each coated pill contains 10 mgm. of the pyridylmethyl carboxylate salt and is an oral dosage unit composition with effective anticholinergic action.

Example 40 Tablets: The tablet composition is compounded from the following ingredients:

Parts l-methyl 1,2,3,6 tetrahydro 4 pyridylmethyl aphenyl-cyclopentylacetate methanesulfonate 6 Lactose 100 Corn starch 64 Soluble starch 8 Magnesium stearate 2 Total 180 Suppositories: The suppository composition is compounded from the following ingredients:

Parts 1-methyl-1,2,3,6 tetrahydro 4 pyridylmethyl aphenyl-cyclohexylacetate methobromide 30 Suppository base (e.g. cocoa butter) 1670 Total 1700 Preparation: The finely pulverized quaternary salt is uniformly blended with the acid of an immersion homogenizer into the suppository base which has previously of the resulting composition are poured at 35 C. into cooled suppository molds. Each suppository contains 30 mgm. of the active ingredient and is a rectal dosage unit composition with effective spasmolytic action.

Example 42 Hypodermic solution: The solution is compounded from the following ingredients:

Parts 1 ethyl-1,2,3,6-tetrahydro-4-pyr.idylmethyl benzilate -HC1 Sodium chloride Distilled water, q.s.ad 2000 parts by vol.

Preparation: The active ingredient and the sodium chloride are dissolved in the boiled, double distilled water, the solution is filtered until free from suspended particles, and the filtrate is filled under aseptic conditions into 2 cc.-ampules, which are subsequently sealed and sterilized for 20 minutes at C. Each ampule contains 1 mgm. of the pyridylmethyl benzilate salt, and its contents are an injectable dosage unit composition with effective spasmolytic action.

Analogous results are obtained when any one of the other tertiary or quaternary compounds of the instant invention is substituted for the particular active ingredient in Examples 39 through 42. Likewise, the amount of active ingredient in the illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements While the present invention has been illustrated with the aid of ,certainspecific embodiments thereof, it will be readily apparent-to others skilled in the art that the invention is not li-mitedto. these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A racemic mixture of a compound of the formula H5 Ru where R is hydroxyl or, together with R and the carbon atoms to which they are attached, a 5- to 6-membered saturated carbocyclic ring,

R and R are each alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 6 carbon atoms or phenyl, and R is cycloalkyl of 5 to 6 carbon atoms or phenyl, an optically active antipode component thereof, a methyl halide, methyl sulfate or methyl methanesulfonate quaternary tetrahydropyridinium salt thereof, or a nontoxic acid addition salt of said racemate or optically active antipode component.

2. A compound of claim 1, which is racemic or opti cally active 1-methyl-1,2,3,6-tetrahydro-4-pyridylmethyl uphenyl-cyclopentylacetate, a nontoxic, pharmacologically acceptable acid addition salt thereof, or the methobromide quaternary salt thereof.

3. A compound of claim 1, which is racemic or optically active l-rnethyl-1,2,3,6-tetrahydro-4-pyridylmethyl aphenyl cyclohexylacetate, a nontoxic, pharmacologically acceptable acid addition salt thereof, or the methobromide quaternary salt thereof.

4. A compound of claim 1, which is racemic or optically active l-ethyl-1,2,3,-6-tetrahydro-4-pyridylmethyl benzilate, a nontoxic, pharmacologically acceptable acid addition salt thereof, or the methobromide quaternary salt thereof.

References Cited Chemical Abstracts, vol. 72, Huebner et al., pp. 377- 378, Item No. 90,298-s, Apr. 27, 1970.

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

260294.8 R, 294.8 B, 295 T; 424-266 UNITED STATES PATENT OFFICE (s/se) CERTIFICATE OF CCRRECTTON Patent No. 3 7 59 January 15, 1974 GERHARD WALTHER, RUDOLF BAUER, HANS-HUGO HUEBNER, ROLF Inventofls) V BANHOLZEB It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 10 line 42, that portion of the fomula which new reads:

F. 9 9 CH -O-Q-C-C-C-OH should read:

CH -0-c-'c-0H 2 Col. 18 line 4 4, after "previously" insert:

- been melted and cooled to 40C and 1700 mgm portions Signed and sealed this 5th day of November 1974..

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

